Graft rejection and graft-versus-host disease remain a significant problem in human allogeneic organ and bone marrow transplantation today, despite tissue matching at the major histocompatibility complex (MHC). These observations suggest the biological importance of "minor" histocompatibility antigenic determinants. The inbred rat has emerged as an important experimental animal model in which to study transplantation immunobiology. The functional and genetic structure of rat "minor" histocompatibility antigens has not been extensively studied. A model has been developed in which alloimmunization between Ag-B compatible rats leads to increased proliferative responses in mixed-lymphocyte-culture (MLC) in normally non-responsive interactions. While augmented MLC responses following alloimmunization occur between Ag-B compatible rat strains, decreased proliferative responses are seen between Ag-B disparate rats. Studies are described in this proposal to elucidate the mechanisms of modulation of MLC responsiveness after allo-immunization between Ag-B compatible rats, and rats which differ only for minor, non-Ag-B histocompatibility loci using congeneic rat strains. The generation of suppressive regulatory mechanisms and possible genetic restrictions of this alloimmunization model system will be investigated. The effects of alloimmune sera on MLC reactivity produced between Ag-B compatible rat strains and congeneic rats will also be studied.